In the production of homogeneous formulations, especially of biologically active substances, the solubilization of hydrophobic, i.e. sparingly water-soluble, substances has gained very great practical significance.
Solubilization is understood to mean the solubilizing of substances which are sparingly soluble or insoluble in a particular solvent, especially water, by interface-active compounds, the solubilizers. Such solubilizers are capable of converting sparingly water-soluble or water-insoluble substances to clear, at most opalescent aqueous solutions, without the chemical structure of these substances undergoing any change in the process (cf. Römpp Chemie Lexikon, 9th edition, vol. 5, p. 4203, Thieme Verlag, Stuttgart, 1992).
In the solubilizates produced, the sparingly water-soluble or water-insoluble substance is present in colloidally dissolved form in the molecular associates of the surface-active compounds which form in aqueous solution, for example, hydrophobic domains or micelles. The resulting solutions are stable or metastable monophasic systems with a visually clear to opalescent appearance.
Solubilizers can, for example, improve the appearance of cosmetic formulations and of food formulations by making the formulations transparent. Moreover, in the case of pharmaceutical formulations, the bioavailability and hence the efficacy of medicaments can be enhanced by the use of solubilizers.
A further desirable requirement on solubilizers is the ability to form so-called “solid solutions” with sparingly soluble substances. The term “solid solution” describes a state in which a substance is distributed in colloidal dispersion or ideally molecular dispersion in a solid matrix, for example, a polymer matrix. Such solid solutions lead, for example, when used in solid pharmaceutical administration forms of a sparingly soluble active ingredient, to improved release of the active ingredient. An important requirement on such solid solutions is that they are stable over a long period even in the course of storage, which means that the active ingredient does not crystallize out. Moreover, the capacity of the solid solution or, in other words, the ability to form stable solid solutions with maximum active ingredient contents is also of significance.
In the formation of solid solutions, in addition to the basic ability of the solubilizers to form solid solutions, the hygroscopicity of the solubilizers also plays an important role. Solubilizers which absorb too much water from the ambient air lead to deliquescence of the solid solution and the undesired crystallization of the active ingredients. In the course of processing to administration forms too, too great a hygroscopicity may present problems.
Many known polymeric solubilizers have the disadvantages that they do not form stable solid solutions. Moreover, they still leave room for improvement as far as solubilization in aqueous systems is concerned. With regard to processability too, some of the known solubilizers, owing to their tendency to tackiness, have disadvantages since they are not sufficiently free-flowing powders.
DE-A 199 350 63 discloses polyalkylene oxide-containing graft polymers, based on vinyllactams and vinyl acetate, and the use thereof as gas hydrate inhibitors.
EP-A 953 347 discloses the use of polyalkylene oxide-containing graft polymers as solubilizers. The graft polymers of vinyl acetate and polyalkylene oxides described there are frequently not a powder, but instead glutinous liquids, which is disadvantageous in application terms.
WO 2007/051743 discloses the use of water-soluble or water-dispersible copolymers of N-vinyllactam, vinyl acetate and polyethers as solubilizers for pharmaceutical, cosmetic, food technology, agrochemical or other industrial applications. It is described in quite general terms therein that the corresponding graft polymers can also be processed with the active ingredients in the melt.
WO 2009/013202 discloses that such graft polymers of N-vinyllactam, vinyl acetate and polyethers can be melted in an extruder and mixed with pulverulent or liquid active ingredients, the extrusion being described at temperatures significantly below the melting point of the active ingredients.
However, mixing of the molten graft polymer with pulverulent or liquid active ingredients cannot achieve satisfactorily high and simultaneously stable active ingredient loading. In particular, the achievement of a stable X-ray-amorphous state of the active ingredient is not always possible to a satisfactory degree.